Virological Failure And HIV-1 Drug Resistance in Indian Adults and Adolescents on Protease Inhibitor Based Second-line Antiretroviral Therapy: A Five-year Follow-up Study.

Abstract

Introduction: In the changing HIV treatment landscape, the focus shifts to persons living with HIV (PLH) experiencing virological non-suppression on second-line antiretroviral therapy (ART). This includes understanding viral genetic profiles, antiretroviral susceptibility, and the effectiveness of protease inhibitors (PIs) amid evolving dolutegravir-based regimen recommendations.

Methods: In this retrospective study, PLH with first-line ART failure transitioned to second-line ART (dual NRTI + ritonavir-boosted PI) between September 2015 and October 2018. Eligible patients were ≥ 13 years old, with ≥ 9 months on first-line ART, and confirmed adherence at first-- line regimen failure. Conducted at a Northern Indian tertiary hospital, this 5 year follow-up examined virological outcomes and drug resistance. Follow-up included initial viral-load (VL) and CD4 testing at 6-months, subsequent VL testing every 6-12 months, clinical evaluations, and infection screenings. Data on demographics, treatment history, virological-failure (VF), and drug-resistance testing (DRT) (Viroseq HIV-1 genotyping-system) were analysed using Kaplan-Meier and Competing-risk analysis, with appropriate censoring and imputation for events like death, transfer-out, treatment discontinuation/ interruption, loss to follow-up (LTFU), or ART-regimen change.

Results: 219 PLH shifted to ritonavir-boosted PI based second-line ART after 68 (median) months (IQR: 68) of first-line ART exposure and were followed up for 57 (median) months (IQR: 48), totalling 11,548 person-months (PM) of follow-up. Virological outcomes were assessed in 201 PLH. VF cumulative-incidence (Kaplan-Meier-analysis) ranged from 6.9% at 36 months to 15.9% at 60 months. Imputation scenarios showed a potential range, with worst-case incidences of 16.2% at 36 months and 29.4% at 60 months. Cumulative-incidence function (CIF) of VF (Competing-risk-analysis) ranged from 6.5% at 36 months to 12.7% at 60 months. Among 171 PLH with complete VL data, VF incidence was 2.7 per 1000 PM (n=29), with 94.7% achieving nadir VL <1000 cp/mL. VF with PI-mutation (VF-M) analysis, including LTFU patients (n=183), showed CIF for VFM of 2.3% at 36 months and 4.9% at 60 months. DRT (n=23-sequences) revealed 17.4% lopinavir resistance, 34.8% atazanvir resistance, and darunavir (DRV) cross-resistance in three sequences. Overall, 26.1% had no significant drug-resistance mutations, 39.1% had NNRTI resistance, but no PI DRMs, and only 34.8% (of 23-PLH who underwent DRT) potentially required third-line ART.

Conclusion: This 5-year longitudinal study highlights the resilience of PIs in second-line ART. The incidence of VF with PI-resistance was notably low, indicating the ongoing effectiveness of PIs in managing PLH on second-line ART and the possibility of recycling PIs in subsequent ART regimens for these patients. Cross-resistance to DRV patients highlights the need for enhanced treatment monitoring.